Explore the vast range of titles available.

ABSTRACT Chlamydiae are pathogenic intracellular bacteria that cause a wide variety of diseases throughout the globe, affecting the eye, lung, coronary arteries and female genital tract. Rather than by direct cellular toxicity, Chlamydia infection generally causes pathology by inducing fibrosis and scarring that is largely mediated by host inflammation. While a robust immune response is required for clearance of the infection, certain elements of that immune response may also damage infected tissue, leading to, in the case of female genital infection, disease sequelae such as pelvic inflammatory disease, infertility and ectopic pregnancy. It has become increasingly clear that the components of the immune system that destroy bacteria and those that cause pathology only partially overlap. In the ongoing quest for a vaccine that prevents Chlamydia-induced disease, it is important to target mechanisms that can achieve protective immunity while preventing mechanisms that damage tissue. This review focuses on mouse models of genital Chlamydia infection and synthesizes recent studies to generate a comprehensive model for immunity in the murine female genital tract, clarifying the respective contributions of various branches of innate and adaptive immunity to both host protection and pathogenic genital scarring. This review summarizes mouse model studies that significantly contributed to our current understanding of the protective and pathogenic immune responses taking place during genital Chlamydia infections.

Key Points Chlamydia spp. are obligate intracellular pathogens that are important causes of human and animal diseases. Chlamydiae share a common developmental cycle in which they alternate between the extracellular, infectious elementary body and the intracellular, non-infectious reticulate body. Chlamydiae use several redundant mechanisms to enter host cells and to establish their intracellular membrane bound niche — the inclusion. Chlamydiae deliver effector proteins into the inclusion membrane and into host cells to promote replication and survival. Chlamydiae encode a unique set of T3SS effectors, the inclusion membrane proteins (Incs), which are inserted into the inclusion membrane where they may function as structural determinants of the membrane or as scaffolds to interface with various cell pathways in the host. Recent studies have solved the 'chlamydial anomaly' and reveal that Chlamydia spp. do synthesize peptidoglycan and use an atypical mechanism of cell division. The recent major advances in chlamydial genetics open the door for the development of tools and avenues of research that were not previously accessible to this historically intractable pathogen. Chlamydia spp. are intracellular bacteria that depend on the host for their metabolic requirements, while hiding from host immune defences. In this Review, Elwell, Mirrashidi and Engel detail the molecular mechanisms that enable these pathogens to shape and thrive in their niche in host cells. Chlamydia spp. are important causes of human disease for which no effective vaccine exists. These obligate intracellular pathogens replicate in a specialized membrane compartment and use a large arsenal of secreted effectors to survive in the hostile intracellular environment of the host. In this Review, we summarize the progress in decoding the interactions between Chlamydia spp. and their hosts that has been made possible by recent technological advances in chlamydial proteomics and genetics. The field is now poised to decipher the molecular mechanisms that underlie the intimate interactions between Chlamydia spp. and their hosts, which will open up many exciting avenues of research for these medically important pathogens.

ABSTRACT Chlamydia trachomatis is the most commonly reported sexually transmitted infection in the United States. The high prevalence of infection and lack of a vaccine indicate a critical knowledge gap surrounding the host's response to infection and how to effectively generate protective immunity. The immune response to C. trachomatis is complex, with cells of the adaptive immune system playing a crucial role in bacterial clearance. Here, we discuss the CD4+ and CD8+ T cell response to Chlamydia, the importance of antigen specificity and the role of memory T cells during the recall response. Ultimately, a deeper understanding of protective immune responses is necessary to develop a vaccine that prevents the inflammatory diseases associated with Chlamydia infection. Here, the authors review the functions by which T cells limit Chlamydia trachomatis infections as well as the ways this pathogen inhibits T cell immunity.

CD4 T cell immune responses such as interferon-γ and tumor necrosis factor-α secretion are necessary for Chlamydia immunity. We used an immunoproteomic approach in which Chlamydia trachomatis and Chlamydia muridarum-derived peptides presented by MHC class II molecules on the surface of infected dendritic cells (DCs) were identified by tandem mass spectrometry using bone marrow derived DCs (BMDCs) from mice of different MHC background. We first compared the C. muridarum immunoproteome in C3H mice to that previously identified in C57BL/6 mice. Fourteen MHC class II binding peptides from 11 Chlamydia proteins were identified from C3H infected BMDCs. Two C. muridarum proteins overlapped between C3H and C57B/6 mice and both were polymorphic membrane proteins (Pmps) which presented distinct class II binding peptides. Next we studied DCs from C57BL/6 mice infected with the human strain, C. trachomatis serovar D. Sixty MHC class II binding peptides derived from 27 C. trachomatis proteins were identified. Nine proteins were orthologous T cell antigens between C. trachomatis and C. muridarum and 2 of the nine were Pmps which generated MHC class II binding epitopes at distinct sequences within the proteins. As determined by antigen specific splenocyte responses outer membrane proteins PmpF, -G and -H and the major outer membrane protein (MOMP) were antigenic in mice previously infected with C. muridarum or C. trachomatis. Furthermore a recombinant protein vaccine consisting of the four Pmps (PmpEFGH) with MOMP formulated with a Th1 polarizing adjuvant significantly accelerated (p<0.001) clearance in the C57BL/6 mice C. trachomatis transcervical infection model. We conclude that Chlamydia outer membrane proteins are important T cell antigens useful in the development of a C. trachomatis subunit vaccine.

Chlamydia trachomatis infection causes severe inflammatory disease resulting in blindness and infertility. The pathophysiology of these diseases remains elusive but myeloid cell-associated inflammation has been implicated. Here we show NLRP3 inflammasome activation is essential for driving a macrophage-associated endometritis resulting in infertility by using a female mouse genital tract chlamydial infection model. We find the chlamydial parasitophorous vacuole protein CT135 triggers NLRP3 inflammasome activation via TLR2/MyD88 signaling as a pathogenic strategy to evade neutrophil host defense. Paradoxically, a consequence of CT135 mediated neutrophil killing results in a submucosal macrophage-associated endometritis driven by ATP/P2X7R induced NLRP3 inflammasome activation. Importantly, macrophage-associated immunopathology occurs independent of macrophage infection. We show chlamydial infection of neutrophils and epithelial cells produce elevated levels of extracellular ATP. We propose this source of ATP serves as a DAMP to activate submucosal macrophage NLRP3 inflammasome that drive damaging immunopathology. These findings offer a paradigm of sterile inflammation in infectious disease pathogenesis. Myeloid cells are implicated in the innate immune and inflammatory response during infection with Chlamydia trachomatis. Here the authors show the evasion of the neutrophil response to infection and concomitant induction of sterile immunity via the purinergic P2X7 receptor.

Natural immunity against obligate and/or facultative intracellular pathogens is usually mediated by both humoral and cellular immunity. The identification of those antigens stimulating both arms of the immune system is instrumental for vaccine discovery. Although high-throughput technologies have been applied for the discovery of antibody-inducing antigens, few examples of their application for T-cell antigens have been reported. We describe how the compilation of the immunome, here defined as the pool of immunogenic antigens inducing T- and B-cell responses in vivo, can lead to vaccine candidates against Chlamydia trachomatis. We selected 120 C. trachomatis proteins and assessed their immunogenicity using two parallel high-throughput approaches. Protein arrays were generated and screened with sera from C. trachomatis-infected patients to identify antibody-inducing antigens. Splenocytes from C. trachomatis-infected mice were stimulated with 79 proteins, and the frequency of antigen-specific CD4⁺/IFN-γ⁺ T cells was analyzed by flow cytometry. We identified 21 antibody-inducing antigens, 16 CD4⁺/IFN-γ⁺-inducing antigens, and five antigens eliciting both types of responses. Assessment of their protective activity in a mouse model of Chlamydia muridarum lung infection led to the identification of seven antigens conferring partial protection when administered with LTK63/CpG adjuvant. Protection was largely the result of cellular immunity as assessed by CD4⁺ T-cell depletion. The seven antigens provided robust additive protection when combined in four-antigen combinations. This study paves the way for the development of an effective anti-Chlamydia vaccine and provides a general approach for the discovery of vaccines against other intracellular pathogens.

Abstract Background Chlamydia trachomatis and Chlamydia muridarum are intracellular bacterial pathogens of mucosal epithelial cells. CD4 T cells and major histocompatibility complex (MHC) class II molecules are essential for protective immunity against them. Antigens presented by dendritic cells (DCs) expand naive pathogen-specific T cells (inductive phase), whereas antigens presented by epithelial cells identify infected epithelial cells as targets during the effector phase. We previously showed that DCs infected by C trachomatis or C muridarum present epitopes from a limited spectrum of chlamydial proteins recognized by Chlamydia-specific CD4 T cells from immune mice. Methods We hypothesized that Chlamydia-infected DCs and epithelial cells present overlapping sets of Chlamydia-MHC class II epitopes to link inductive and effector phases to generate protective immunity. We tested that hypothesis by infecting an oviductal epithelial cell line with C muridarum, followed by immunoaffinity isolation and sequencing of MHC class I- and II-bound peptides. Results We identified 26 class I-bound and 4 class II-bound Chlamydia-derived peptides from infected epithelial cells. We were surprised to find that none of the epithelial cell class I- and class II-bound chlamydial peptides overlapped with peptides presented by DCs. Conclusions We suggest the discordance between the DC and epithelial cell immunoproteomes has implications for delayed clearance of Chlamydia and design of a Chlamydia vaccine. Optimally, DCs expand antigen-specific naive T cells that recognize infected cells. We tested this postulate by determining the Chlamydia-epithelial immunoproteome. Chlamydia antigens presented to CD4 T cells by DC and epithelial cells are discordant, with major implications for vaccine development.

•78 million new infections annually; greatest impact on women and neonates in LMIC.•Current control measures are inadequate and challenged by antibiotic resistance.•Conserved candidate vaccine antigens and adjuvant strategies are being developed.•There is a need for human studies to investigate correlates of immunity.•A meningococcal outer membrane vesicle vaccine may protect against gonorrhea. There is a growing public health interest in controlling sexually transmitted infections (STIs) through vaccination due to increasing recognition of the global disease burden of STIs and the role of STIs in women’s reproductive health, adverse pregnancy outcomes, and the health and well-being of neonates. Neisseria gonorrhoeae has historically challenged vaccine development through the expression of phase and antigenically variable surface molecules and its capacity to cause repeated infections without inducing protective immunity. An estimated 78 million new N. gonorrhoeae infections occur annually and the greatest disease burden is carried by low- and middle-income countries (LMIC). Current control measures are clearly inadequate and threatened by the rapid emergence of antibiotic resistance. The gonococcus now holds the status of “super-bug” as there is currently no single reliable monotherapy for empirical treatment of gonorrhea. The problem of antibiotic resistance has elevated treatment costs and necessitated the establishment of large surveillance programs to track the spread of resistant strains. Here we review the need for a gonorrhea vaccine with respect to global disease burden and related socioeconomic and treatment costs, with an emphasis on the impact of gonorrhea on women and newborns. We also highlight the challenge of estimating the impact of a gonorrhea vaccine due to the need for more data on the burden of gonococcal pelvic inflammatory disease and related sequelae and of gonorrhea-associated adverse pregnancy outcomes and the problem of empirical diagnosis and treatment of STIs in LMIC. There is also a lack of clinical and basic science research in the area of gonococcal/chlamydia coinfection, which occurs in a high percentage of individuals with gonorrhea and should be considered when testing the efficacy of gonorrhea vaccines. Finally, we review recent research that suggests a gonorrhea vaccine is feasible and discuss challenges and research gaps in gonorrhea vaccine development.

Chlamydiosis is a significant disease affecting Eastern Australian koalas ( Phascolarctos cinereus ), contributing to the decline of some koala populations, necessitating investigations into appropriate management strategies to address chlamydiosis in wild koala populations. The aim of this study was to investigate the effect of a Chlamydia pecorum recombinant Major Outer Membrane Protein (rMOMP) vaccine as a potential strategy for managing chlamydiosis at a population level. This study comprised a blinded, randomised placebo-controlled trial, encompassing different koala populations where chlamydiosis is having differing effects. Wild koalas were recruited into a vaccination or a placebo treatment group and followed for 12 months, with recapture and resampling at 2, 6 and 12 months post vaccination. Vaccination stimulated a significant plasma anti-MOMP IgG response and greater IL-17 and TNFα mRNA fold change from rMOMP stimulated leukocytes, however, did not boost pre-existing immune responses, from natural infection, in koalas. The observed immunological stimulation did not translate to any effect on chlamydiosis or chlamydial shedding in our study populations. These findings highlight the necessity of improving our understanding of what constitutes a protective immune response in koalas to guide the development of a more effective vaccine. This study evaluated the estimated effect of vaccination necessary to achieve management outcomes predicted by modelling studies. It is possible that vaccination has a more modest effect and could benefit koala populations with a lower disease prevalence or be useful in conjunction with additional management strategies.